Christelle D'Sa, Class of 2022
Human Immunodeficiency Virus Type 1(HIV-1) is commonly known as the virus that causes the HIV infection. It can spread through any type of bodily fluid and it is a life long disease (7). HIV contains a protein called reverse transcriptase, which is how it can so effectively target white blood cells, also known as T cells (6). HIV attaches to a CD4+ receptor on the T cell and can then infect that cell (1). After injecting the T cell with its viral RNA and reverse transcriptase, the reverse transcriptase uses viral RNA and the material in the cell to create new viral DNA. Once this viral DNA enters the nucleus the cell starts to create new HIV-1 viruses, which eventually escape the cell to start the whole process over again. However, before these cells burst, CD8+ T cells can recognize them and can kill the cell (4). This successfully stops the HIV-1 virus from infecting other cells.
Currently, HIV-1 is mostly treated with antiretroviral therapy (ART) and other HIV medicines. ART prevents a retrovirus from replicating and so reduces the symptoms of HIV in patients. The most common symptoms of HIV are fevers, rashes, and/or chills. HIV specifically targets the immune system, so a person with HIV will eventually develop Acquired Immune Deficiency Syndrome (AIDS) where the immune system is very weak and cannot defend the body effectively (8).
Recently, a group of scientists found that patients who underwent a combination of anti-HIV-1 antibody therapy also increased certain T cells’ ability to fight against HIV-1 viruses (5). Broadly neutralizing antibodies (bNabs) are antibodies that recognize and prevent HIV viruses from entering cells. It is for this reason that they could be an alternative to ART or used concurrently with it. These scientists wanted to see whether bNabs would be effective in treating patients with HIV-1.
In a clinical trial, patients who had HIV-1 and were currently on ART received two bNabs at 0, 3, and 6 weeks. After the first two days, they stopped ART. Nine people experienced HIV-1 suppression at 15 weeks after the interruption of ART and the treatment with the bNabs. Levels and responses of CD4+ and CD8+ T cells were also tracked by their cytokine expression because their levels are affected by the HIV-1 virus. Individuals on ART had either stable or decreasing levels of CD4+ and CD8+ T responses. Individuals with the bNab treatment saw increased levels of CD8+ and CD4+ T cell levels after 6-7 weeks. This means that their immune systems were more actively seeking and destroying HIV viruses and the infected cells that were producing those viruses. Decreasing levels of these cells would indicate that the immune system was becoming less responsive to the HIV virus and that there were more viruses being produced. The CD8+ levels slightly decreased in some individuals after 12 weeks but were still above those on ART. After week 12, CD8+ and CD4+ response levels were still about the same (5).
Additionally, these scientists also wanted to see whether polyfunctional HIV-1 specific CD8+ T cells, which supposedly increase the degree of control the body has over HIV-1 levels, would also be affected by the addition of bNabs and the interruption of ART. They found that the greatest increase in CD8+ responses happened in conjunction with cells that expressed MIP1-β+, a type of inflammatory protein which has antiviral functions (3). Additionally, it was found that CD4+ cells with certain markers also increased during this time period relative to the baseline for individuals who were treated with bNabs (5). This increase in CD4+ cells above the baseline meant that this type of treatment was more effective and allowed the CD4+ cells to avoid being infected by the HIV virus. This also indicates that the inflammatory protein and CD8+ cell levels indirectly affected CD4+ levels, creating a more robust immune system.
To confirm these findings, they used activation-induced markers (AIM) assays which find active T-cells that are harder to identify. Previously, the scientists had tracked the number of active T cells by searching for a specific type of cytokine expressed by these immune cells. However, different T cells express different types of cytokines while others express none at all (5). This can lead to a decrease in the number of active CD8+ and CD4+ T cells observed. The AIM assay confirmed their previous findings. They also found that T cell responses were aimed at new epitopes, signaling molecules that trigger immune responses, in individuals who had undergone bNab therapy (2).
Finally, they used HIV-1 viral inhibition assays to determine if the increased HIV-1 specific T cell response could subdue cells infected with HIV-1 in vitro. Only the cell cultures from one of the two participants showed significant suppression of HIV-1 at week 12 (5). While the sample size for this part of the experiment was small, it may indicate that the HIV-1 virus specific response increase seen in the previous paragraphs is not applicable to cells infected with HIV-1 in vitro. Instead, the bNab treatment may only work for a specific portion of the population that was infected with the HIV-1 virus later in life.
The scientists ultimately found that stopping ART and receiving bNab therapy resulted in increased T cell immunity to HIV-1 in some of the participants. This could potentially mean that bNab therapy with ART interruption could become more common in treating HIV-1 in the future. However, it is unlikely that it will completely replace ART.
References
Picture: madartzgraphics. 2016. pixabay. pixabay. [accessed 2020 Feb 15]. https://pixabay.com/illustrations/hiv-aids-virus-disease-health-1903373/
Currently, HIV-1 is mostly treated with antiretroviral therapy (ART) and other HIV medicines. ART prevents a retrovirus from replicating and so reduces the symptoms of HIV in patients. The most common symptoms of HIV are fevers, rashes, and/or chills. HIV specifically targets the immune system, so a person with HIV will eventually develop Acquired Immune Deficiency Syndrome (AIDS) where the immune system is very weak and cannot defend the body effectively (8).
Recently, a group of scientists found that patients who underwent a combination of anti-HIV-1 antibody therapy also increased certain T cells’ ability to fight against HIV-1 viruses (5). Broadly neutralizing antibodies (bNabs) are antibodies that recognize and prevent HIV viruses from entering cells. It is for this reason that they could be an alternative to ART or used concurrently with it. These scientists wanted to see whether bNabs would be effective in treating patients with HIV-1.
In a clinical trial, patients who had HIV-1 and were currently on ART received two bNabs at 0, 3, and 6 weeks. After the first two days, they stopped ART. Nine people experienced HIV-1 suppression at 15 weeks after the interruption of ART and the treatment with the bNabs. Levels and responses of CD4+ and CD8+ T cells were also tracked by their cytokine expression because their levels are affected by the HIV-1 virus. Individuals on ART had either stable or decreasing levels of CD4+ and CD8+ T responses. Individuals with the bNab treatment saw increased levels of CD8+ and CD4+ T cell levels after 6-7 weeks. This means that their immune systems were more actively seeking and destroying HIV viruses and the infected cells that were producing those viruses. Decreasing levels of these cells would indicate that the immune system was becoming less responsive to the HIV virus and that there were more viruses being produced. The CD8+ levels slightly decreased in some individuals after 12 weeks but were still above those on ART. After week 12, CD8+ and CD4+ response levels were still about the same (5).
Additionally, these scientists also wanted to see whether polyfunctional HIV-1 specific CD8+ T cells, which supposedly increase the degree of control the body has over HIV-1 levels, would also be affected by the addition of bNabs and the interruption of ART. They found that the greatest increase in CD8+ responses happened in conjunction with cells that expressed MIP1-β+, a type of inflammatory protein which has antiviral functions (3). Additionally, it was found that CD4+ cells with certain markers also increased during this time period relative to the baseline for individuals who were treated with bNabs (5). This increase in CD4+ cells above the baseline meant that this type of treatment was more effective and allowed the CD4+ cells to avoid being infected by the HIV virus. This also indicates that the inflammatory protein and CD8+ cell levels indirectly affected CD4+ levels, creating a more robust immune system.
To confirm these findings, they used activation-induced markers (AIM) assays which find active T-cells that are harder to identify. Previously, the scientists had tracked the number of active T cells by searching for a specific type of cytokine expressed by these immune cells. However, different T cells express different types of cytokines while others express none at all (5). This can lead to a decrease in the number of active CD8+ and CD4+ T cells observed. The AIM assay confirmed their previous findings. They also found that T cell responses were aimed at new epitopes, signaling molecules that trigger immune responses, in individuals who had undergone bNab therapy (2).
Finally, they used HIV-1 viral inhibition assays to determine if the increased HIV-1 specific T cell response could subdue cells infected with HIV-1 in vitro. Only the cell cultures from one of the two participants showed significant suppression of HIV-1 at week 12 (5). While the sample size for this part of the experiment was small, it may indicate that the HIV-1 virus specific response increase seen in the previous paragraphs is not applicable to cells infected with HIV-1 in vitro. Instead, the bNab treatment may only work for a specific portion of the population that was infected with the HIV-1 virus later in life.
The scientists ultimately found that stopping ART and receiving bNab therapy resulted in increased T cell immunity to HIV-1 in some of the participants. This could potentially mean that bNab therapy with ART interruption could become more common in treating HIV-1 in the future. However, it is unlikely that it will completely replace ART.
References
Picture: madartzgraphics. 2016. pixabay. pixabay. [accessed 2020 Feb 15]. https://pixabay.com/illustrations/hiv-aids-virus-disease-health-1903373/
- Cossins D. 2013 Dec 19. How HIV Destroys Immune Cells. The Scientist Magazine®. [accessed 2020 Feb 15]. https://www.the-scientist.com/daily-news/how-hiv-destroys-immune-cells-38230
- Epitope. Merriam-Webster. [accessed 2020 Feb 15]. https://www.merriam-webster.com/dictionary/epitope
- Gemini Bio. 2012 Jan 6. Mouse Macrophage Inflammatory Protein-1 beta (MIP-1 β / CCL4). Gemini Bio. [accessed 2020 Feb 15]. https://www.gembio.com/product/mouse-macrophage-inflammatory-protein-1-beta-mip-1-b-ccl4
- Gulzar N, Copeland KFT. 2004 Jan. CD8 T-cells: function and response to HIV infection. Current HIV research. [accessed 2020 Feb 15]. https://www.ncbi.nlm.nih.gov/pubmed/15053338/
- Niessl J, Baxter AE, Mendoza P, Jankovic M, Cohen YZ, Butler AL, Lu C-L, Dubé M, Shimeliovich I, Gruell H, et al. 2020 Feb 3. Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity. Nature News. [accessed 2020 Feb 15]. https://www.nature.com/articles/s41591-019-0747-1
- TheBody. 2008 Sep 18. How HIV Damages the Immune System. The Complete HIV/AIDS Resource - TheBody.com. [accessed 2020 Feb 15]. https://www.thebody.com/article/hiv-damages-immune-system
- U.S. Department of Health & Human Services. 2020 Feb 13. HIV. Centers for Disease Control and Prevention. [accessed 2020 Feb 15]. https://www.cdc.gov/hiv/default.html
- U.S. Department of Health and Human Services. 2019 Jul 3. HIV/AIDS: The Basics Understanding HIV/AIDS. National Institutes of Health. [accessed 2020 Feb 15]. https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/45/hiv-aids--the-basics
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